Colon cleansing is important prior to numerous diagnostic and surgical procedures, for example before colonoscopy, barium enema examination or colon surgery. It is also useful for preventing infection after surgery on the lower intestine. Colon cleansing is also known as colon clearing.
A variety of methods for colon cleansing are known. Dietary manipulation, laxatives, cathartics and enemas were traditionally used (Thomas, G. et al., Gastroenterology, 1982, 82, 435-437). Sodium phosphate solutions (Clarkston, W. K. et al., Gastrointestinal Endoscopy, 1996, 43, 43-48) and magnesium citrate/sodium picosulphate solutions (Regev, A. et al., Am. J. Gastroenterol., 1998, 93, 1478-1482) have also been used.
Those methods suffer from various drawbacks. Dietary manipulation and laxatives are time consuming; enemas are unpleasant for the patient; and dangerous salt and water losses may occur with cathartics, enemas and with sodium phosphate solutions.
Sodium phosphate solutions, such as that available from C.B. Fleet Company Inc. (4615 Murray Place, PO Box 11349, Lynchburg, Va. 24506, USA) under the trade name Phospho-soda® are hyperosmotic solutions which increase retention of water in the intestine and thereby promote bowel movement. Phospho-soda comprises, per 5 ml portion, 2.4 g monobasic sodium phosphate monohydrate with 0.9 g dibasic sodium phosphate heptahydrate in a buffered aqueous solution. Typically 20 to 45 ml are taken by an adult patient followed by a large quantity of water. If the water is not taken, elevated serum sodium and phosphate levels may result, leading to serious kidney problems. The risk of those side effects makes it necessary for there to be direct medical supervision during administration of Phospho-soda.
Another approach to colon cleansing is orthostatic intestinal lavage, in which a large volume of an electrolyte solution is ingested, either by drinking or by infusion through a nasogastric tube. Such lavage solutions are also known as bowel lavage solutions. Consumption of the solution results in volume-induced diarrhoea and thus cleansing of the colon. The method is generally faster than the traditional approaches. The main component of early lavage solutions was sodium chloride. However, as a significant percentage of such saline-based lavage solutions is absorbed into the bloodstream in the gut of the patient, a rapid increase in intravascular volume results, which has caused serious complications in some patients.
In 1980, Davis and co-workers reported the development of a lavage solution, that they described as being associated with minimal water and electrolyte absorption or secretion (Davis G. R. et al., Gastroenterology, 1980, 78, 991-995). The solution included sodium sulphate and polyethylene glycol. Sulphate ions are poorly absorbed in the gut. As a result, sodium absorption is markedly reduced when sulphate, rather than chloride or bicarbonate, is the predominant counter-anion present in a lavage solution in the gut. In addition to sodium sulphate (40.0 mM, 5.68 g/l), the solution described by Davis et al. comprises sodium chloride (25 mM, 1.463 g/l), potassium chloride (10 mM, 0.745 g/l), sodium bicarbonate (20 mM, 1.680 g/l), polyethylene glycol (PEG 4000 “carbowax”, 64 g/l) and water. The solution was administered in a quantity of 4 liters. The solution was shown to be effective in cleansing the gastrointestinal tract and it has been commercialised under the trade name GoLYTELY® (Braintree Laboratories Inc, Braintree, Mass., U.S.A.). The commercially available GoLYTELY composition, also known as Klean Prep®, as available after August 1996 and at the time of filing, is supplied in dry powder form comprising sodium sulphate (40.0 mM, 5.685 g/l), sodium chloride (25 mM, 1.464 g/l), potassium chloride (10 mM, 0.743 g/l), sodium bicarbonate (20 mM, 1.685 g/l) and PEG 3350 polyethylene glycol (59 g/l) for making up to 4 liters. GoLYTELY is also supplied in aqueous solution.
The GoLYTELY solution, whilst effective, has a very salty taste, which adversely affects patient compliance. Typically the composition is presented as four or more liters of aqueous solution, and it is important that the whole prescribed volume is consumed. Consumption of such large volumes of fluid can also affect compliance adversely.
Fordtran et al. (WO87/00754) subsequently developed a reduced sodium sulphate solution (RSS) comprising no sodium sulphate but instead having a relatively high concentration of polyethylene glycol (75 to 300 g/l). The preferred solution disclosed in WO87/00754 comprises PEG 3350 (120 g/l), sodium bicarbonate (1.68 g/l), potassium chloride (0.74 g/l) and sodium chloride (1.46 g/l) and it is also administered in a quantity of 4 liters. A solution very similar to the preferred solution of WO87/00754 is commercialised by Braintree Laboratories Inc (Braintree, Mass., U.S.A.) under the name NuLYTELY® (initially also under the name GoLYTELY-RSS). The NuLYTELY composition comprises PEG 3350 (105 g/l), sodium bicarbonate (1.43 g/l), potassium chloride (0.37 g/l) and sodium chloride (2.80 g/l) and it is supplied in dry powder form for making up to 4 liters.
Whilst being effective in colon cleansing in the clinic, both the GoLYTELY and the NuLYTELY solutions must be ingested in large quantities, typically four liters. Ingestion of such volumes of gut lavage solution is generally physically unpleasant or even impossible for many patients, may result in retching, and is time consuming. In spite of the absence of sodium sulphate in NuLYTELY, both NuLYTELY and GoLYTELY have an unpleasant salty taste. The unpleasant taste exacerbates the problem of patient compliance, particularly when the patient is not under medical supervision.
In WO 89/05659 (Borody) there is described an orthostatic lavage solution comprising polyethylene glycol, electrolytes and from 0.25 to 50 g/l ascorbic acid (vitamin C) or a salt thereof. The presence of ascorbic acid or a salt thereof is said to reduce the required volume of solution to 3 liters or less. Whilst about 3 g of ascorbic acid may be absorbed in the intestine (Hornig, D. et al., Int. J. Vit. Nutr. Res., 1980, 50, 309) any further ascorbic acid is reported in WO 89/05659 to contribute to the diarrhoea and to inhibit bacterial gas generation and bacterial reproduction. The ascorbic acid is also said to facilitate ingestion of the lavage solution because its pleasant acidic taste masks the usual nauseating taste of the salty polyethylene glycol solution.
The solutions described by Borody comprise polyethylene glycol (preferably PEG 3350 or PEG 4000) at a concentration of 30-60 g/liter together with inorganic electrolytes (sodium chloride, potassium chloride, sodium hydrogen carbonate and sodium sulfate). In any given solution, the quantity of PEG is described as being adjusted such that the osmolarity of the solution is approximately 289 mOsmol/kg (i.e. isotonic). The osmolarity of a solution may be measured using conventional laboratory techniques. It is also possible to calculate osmolarity from a knowledge of the components of a solution. Details of osmolarity calculations are given herein below.
A formulation as described by Borody has been available on the market in Australia for more than 10 years under the tradename GLYCOPREP C (Pharmatel). The GLYCOPREP C dry composition comprises PEG 3350 (53 g/l), sodium chloride (2.63 g/l), potassium chloride (0.743 g/l), sodium sulphate (5.6 g/l), ascorbic acid (6 g/l), aspartame (0.360 g/l), citric acid (0.900 g/l) and lemon flavour (0.090 g/l). 3 liters of the solution are generally administered.
Whilst the addition of ascorbic acid goes some way towards providing an improved bowel preparation, that preparation must be ingested in quantities of approximately 3 liters. Ingestion of such volumes of gut lavage solution is still generally physically unpleasant or, for some patients, even impossible, may result in retching, and is time consuming. Accordingly there remains a requirement for lavage solutions with a more pleasant taste that are effective in a smaller volume.
Colon clearance is important before numerous surgical or diagnostic procedures, including colonoscopy, barium enema examination, sigmoidoscopy and colon surgery. It is desirable that the colon clearance may be carried out by the patient himself or herself without medical supervision at home in advance of attending the hospital or surgery where the surgical or diagnostic procedure is to take place. It is important that patient compliance is good without medical supervision if satisfactory colon clearance is to be achieved.
The compositions of the prior art are summarised in Table 1. In that table, the indicated quantities are the quantities present per liter of aqueous solution. The calculated osmolarity of the solutions (in mOsmol/kg) is also given in the table together with the recommended dose (in liters).
TABLE 1Composition of prior art colon cleansing treatmentsFormulationPEG gNa2SO4 gNaHCO3 gNaCl gKCl gVit C gOsmVol 1GoLYTELY605.71.931.460.75—2554NuLYTELY105—1.432.80.37—1764Glycoprep C535.6—2.630.746.02913